Combination of topical kinase inhibitors to achieve synergistic clearance of skin cancers and related lesions

Abstract

The present invention provides methods for treating an early-stage skin cancer in situ or a noninvasive precancerous lesion, as well as an invasive skin cancer lesion. Also provided are methods for inducing regression or achieving clearance of the lesion in a subject by topically administering a therapeutically effective amount of a combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor. The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of a combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor.

Description

P-637213-PC COMBINATION OF TOPICAL KINASE INHIBITORS TO ACHIEVE SYNERGISTIC CLEARANCE OF SKIN CANCERS AND RELATED LESIONS STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0001] This invention was made with government support under ES028114 awarded by the National Institutes of Health. The government has certain rights in the invention. FIELD OF THE INVENTION

[0002] The present invention provides methods for treating an early-stage skin cancer in situ or a noninvasive precancerous lesion, as well as methods for inducing regression or achieving clearance of the lesion, in a subject by topically administering a combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor. The present invention also provides pharmaceutical compositions comprising a combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor. BACKGROUND OF THE INVENTION

[0003] UV-induced skin lesions, such as actinic keratoses (AKs) and squamous cell carcinoma in situ (SCCIS) are the most common pre-cancerous lesions in humans with an estimated 50-60 million lesions per year in the United States. These lesions consist of thick, scaly, or crusty patches of skin and occur primarily in fair-skinned people with a history of sun-exposure. Individually, a low percentage of these pre-cancers (0.1-0.5%) may progress to invasive squamous cell carcinoma, though as persons develop more of these lesions the risk of malignant transformation rises significantly.

[0004] There are a range of treatments available for AKs and SCCIS, but the currently available treatments are associated with prominent skin irritation and are only moderately effective. For example, a topical therapy for AKs containing 5-fluorouracil, a chemotherapy agent, exhibits prominent side effects including irritation, pain, inflammation, erosions, and scarring which often limits clinical efficacy because patients do not complete the full course of treatment. Similarly, imiquimod is an immune enhancing topical agent used to treat AKs and warts, but this treatment is expensive and irritating due to the inflammatory response it elicits. Diclofenac sodium 3% gel, a nonsteroidal anti-inflammatory drug, is even less effective and requires longer treatment courses than topical 5-fluorouracil and topical imiquimod. Other treatments for AKs include cryosurgery with liquid nitrogen, photodynamic therapy, laser treatment, electrocautery, as well as variousP-637213-PC forms of surgery that are known to cause physical discomfort, have higher costs associated with performing procedures and produce inferior cosmetic outcomes. Given these persistent issues, there remains an unmet medical need for developing improved drug compositions to treat non- invasive precancerous skin lesions, skin tumors, and their associated diseases or disorders, as well as for methods of treating precancerous skin lesions and achieving clearance of such non-invasive skin cancer or precancerous lesions, including but not limited to actinic keratoses and squamous cell carcinoma in situ. SUMMARY OF THE INVENTION

[0005] In one aspect, provided herein is a method for treating an early-stage skin cancer in situ or a noninvasive precancerous lesion in a subject in need thereof, the method comprising topically administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor.

[0006] In another aspect, provided herein is a method for inducing regression or achieving clearance of an early-stage skin cancer in situ or a noninvasive precancerous lesion in a subject in need thereof, the method comprising topically administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor.

[0007] In one aspect, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor, and a pharmaceutically acceptable carrier. In still another aspect, provided herein is a spray-on patch for treating an early-stage skin cancer in situ or a noninvasive precancerous lesion, the spray-on patch comprising a pharmaceutical composition comprising a therapeutically effective amount of a combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor. In yet another aspect, provided herein is a transdermal patch for treating an early-stage skin cancer in situ or a noninvasive precancerous lesion, the transdermal patch comprising a pharmaceutical composition comprising a therapeutically effective amount of a combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor.

[0008] In one aspect, provided herein is a method for treating an invasive skin cancer lesion in a subject in need thereof, the method comprising topically administering to the subject a therapeutically effective amount of a combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor. In one aspect, provided herein is a method for inducing regression or remission of anP-637213-PC invasive skin cancer lesion in a subject in need thereof, the method comprising topically administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor.

[0009] Other features and advantages of the present invention will become apparent from the following detailed description, examples, and figures. It should be understood, however, that the detailed description and the specific examples while indicating certain embodiments of the invention are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure, the inventions of which can be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

[0011] Figure 1 shows a combination of dasatinib (Das) 0.5% and birmiralisib (Birm) 0.3% topical kinase inhibitors to treat cSCCs in K14-Fyn Y528F transgenic mouse, an in vivo model of human UV-induced skin cancer. Topical kinase inhibitors were applied once per day to cSCCs and the area of the lesions was measured as a function of time. The combination of topical kinase inhibitors performed significantly better than each agent alone. Number of cSCCs treated per cohort: dasatinib-17, birmiralisib-20, combination-17.

[0012] Figure 2 shows a combination of dasatinib (Das) 0.25% and 0.8% vemurafenib (Vemu) vs 0.5% dasatinib (Das) and 0.5% birmiralisib (Birm) topical kinase inhibitors to treat cSCCs in K14- Fyn Y528F transgenic mouse. The topical kinase inhibitors were applied once per day to cSCCs and the area of the lesions was measured as a function of time. The combination of topical kinase inhibitors with vemurafenib is much less efficient in clearing lesions.

[0013] Figure 3 shows a summary of a combination of dasatinib (Das) 0.25% and 0.8% vemurafenib (Vemu) vs 0.5% dasatinib (Das) and either 0.3% birmiralisib (Birm) or 0.3% buparlisib (Bupa) vs single agent topical kinase inhibitors to treat cSCCs in K14-Fyn Y528F transgenic mouse. The topical kinase inhibitors were applied once per day to cSCCs and the area of the lesions was measured as a function of time. The combination of topical kinase inhibitors with vemurafenib is much less efficient in clearing lesions.P-637213-PC

[0014] Figure 4 shows a single dose of topical dasatinib 2% and buparlisib 2% induces significant regression of cSCCs in one week in K14 Fyn Y528F mice. A single dose of 2.0% dasatinib and 2.0% buparlisib was applied topically to cSCCs at day 0. Tumor area was measured at time 0 and at days 1, 3, 7 and 28. The average tumor area was plotted plus / minus the standard error. p value at day 0 vs 7 is indicated. N=15. DETAILED DESCRIPTION OF THE INVENTION

[0015] The present subject matter may be understood more readily by reference to the following detailed description which forms a part of this disclosure. It is to be understood that this invention is not limited to the specific products, methods, conditions or parameters described and / or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed invention.

[0016] Early treatment of small, scaly patches, known as actinic keratoses (AKs), is recommended to prevent the development of squamous cell skin carcinoma, which has significantly increased morbidity and potential for aggressive behavior including metastasis. Similarly, actinic cheilitis (Farmer’s Lip), presenting as scaly patches or persistent roughness of the lips, a precancerous condition that typically appears on the lower lips, may develop into invasive squamous cell skin carcinoma if not treated. Another type of AK is a cutaneous horn / hypertrophic AK, that appears as a funnel-shaped growth extending from the base of the skin, and squamous cell skin carcinoma is found at the base. Early diagnosis and treatment of non-invasive precancerous lesions caused by UV damage, e.g., from sun exposure or indoor tanning, may prevent development of nonmelanoma squamous cell skin carcinoma, including Bowen’s disease.

[0017] Local therapy for precancerous skin lesions such as AKs, include cryosurgery, photodynamic therapy, topical chemotherapy, and surgery. Cryosurgery involves applying liquid nitrogen to the skin lesion and often requires multiple rounds of treatments; such freezing and killing of precancerous cells typically leaves a scar and the treated area of the skin may have less color (pigmentation) after cryosurgery. Photodynamic therapy (PDT), which used to treat AKs and early forms of squamous cell cancer (known as squamous cell carcinoma in situ, or Bowen disease) requires application of a drug in liquid or gel form that renders the precancerous skin cells very sensitive to certain types of light, followed by treatment with a special light source to kill such noninvasive types of skin lesions. PDT causes redness and swelling of the treated area of skin and may cause a patient’s skin to become very sensitive to sunlight for an extended time period. PDTP-637213-PC also requires significant time in a medical office for administration of the photosensitizing drug followed by a waiting period and then exposure to the blue light. PDT is significantly more time consuming than applying a topical agent. Topical chemotherapy for precancerous skin lesions such as AKs, includes 5-fluorouracil, Tirbanibulin (Klisyri), and Diclofenac (Solaraze).

[0018] 5-fluorouracil, which requires application one or twice per day for several weeks also causes redness and swelling of the treated area and may result in the skin becoming more sensitive to sunlight. Tirbanibulin, which is applied to the skin lesion once per day for five days, can cause pain or itching in the treated area, but may also have side effects, such as swelling, redness, flaking, scaling or peeling of the skin, sores and blisters, and even breakdown of the skin. Diclofenac, which is a nonsteroidal anti-inflammatory drug that may be used to treat AKs by applying a gel form twice daily for two to three months, may cause fewer side effects than 5-fluorouracil and Tirbanibulin, but requires a longer treatment time period.

[0019] AKs and very early basal cell cancers may be treated with immune modifiers, such as imiquimod cream, by application a few time per week over several weeks, which also causes skin reactions, as well as possible flu-like symptoms. Laser surgery may be used to treat AKs, squamous cell carcinoma in situ and very superficial basal cell cancers. Likewise, chemical peeling by applying trichloroacetic acid to the precancerous skin lesion may be used to treat AKs, but also results in side effects, such as redness, dyspigmentation and skin peeling in the treated area.

[0020] The present invention provides a unique topical approach for the treatment of early-stage UV-induced skin cancers and precancerous lesions, typically called actinic keratoses, using combinations of topical kinase inhibitors that exhibit a synergistic effect in an in vivo skin cancer model (Examples 1-4). The studies described herein have identified novel combinations of topical kinase inhibitors that treat actinic keratoses (AKs) and squamous cell carcinoma in situ (SCCIS) in a rapid and effective manner with minimal adverse side effects. Specifically described and provided herein are compositions comprising novel combinations of a tyrosine kinase inhibitor with a PI3K / mTOR inhibitor and therapeutic methods for treating precancerous skin lesions, skin tumors, and their associated diseases or disorders. The combination topical kinase inhibitors provided herein will normalize keratinocyte hyperproliferation seen in actinic keratoses / SCCIS and therefore, can be useful in treating skin disorders associated with keratinocyte hyperproliferation, including but not limited to, psoriasis, lichen simplex chronicus, seborrheicP-637213-PC keratoses, porokeratosis, lichen planus, verrucae (warts), and related disorders. Such combination topical kinase inhibitors may also be used to treat all epidermal proliferation.

[0021] Specifically described and provided herein are methods comprising topically administering a therapeutically effective amount of a combination of a tyrosine kinase inhibitor, for example, a Src family tyrosine kinase (SFK) inhibitor, and a PI3K / mTOR inhibitor to a subject in need thereof resulting in the treatment of the skin lesion in the subject. The methods of treatment by topically administering the combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor induce regression or achieve clearance of early-stage skin cancer in situ or a noninvasive precancerous lesion in a subject in need thereof in a rapid and more effective manner compared to topical administration of a single agent of the tyrosine kinase inhibitor or the PI3K / mTOR inhibitor with minimal undesirable side effects (Examples 1 and 3). In an embodiment of said methods, topically administering a single dose of a combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor at high concentrations of each respective inhibitor significantly reduces tumor size of early-stage skin cancer in situ or a noninvasive precancerous lesion (Example 4).

[0022] The greater efficacy of the combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor in inducing regression of cutaneous squamous cell carcinoma lesions in the K14 Fyn Y528F transgenic mouse model of skin cancer than by applying a single agent was surprising and unexpected in view of the complexity of signaling pathways in keratinocytes and the observation that a tyrosine kinase inhibitor combined with a MAP kinase inhibitor did not produce such synergy. Specifically, it was not clear whether the combination of these two compounds together would induce quicker tumor regression, because the PI3K / mTOR inhibitor acts downstream of tyrosine kinases.

[0023] In one aspect, the present invention provides a method for treating an early-stage skin cancer in situ or a noninvasive precancerous lesion in a subject in need thereof, the method comprising topically administering to the subject a therapeutically effective amount of a combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor. In an embodiment of the method, the tyrosine kinase inhibitor is a compound with strong specificity for Src family tyrosine kinases, an SFK inhibitor. In some embodiments, the tyrosine kinase inhibitor is selected from, but is not limited to, the group consisting of Dasatinib, Ponatinib, Saracatinib, Bosutinib, Rebastinib, Masitinib, Tirbanibulin, Bafetinib, SU6656 and Elzovanitinib, and the PI3K / mTOR inhibitor is selected from, but is not limited to, the group consisting of bimiralisib (PQR309),P-637213-PC Umbralisib, Buparlisib, PIK-75 hydrochloride, AZD 6482, VS-5584, Pilaralisib, SAR-260301, Acalisib, Copanlisib, Pictilisib, Dactolisib, Inavolisib, Idelalisib, Duvelisib, Omipalisib, Taselisib and Voxtalisib. In some embodiments, the tyrosine kinase inhibitor is dasatinib and the PI3K / mTOR inhibitor is bimiralisib (PQR309). In some embodiments, the tyrosine kinase inhibitor is dasatinib and the PI3K / mTOR inhibitor is buparlisib. In an embodiment, the early- stage skin cancer in situ or the noninvasive precancerous lesion is actinic keratosis. In some embodiments, the early-stage skin cancer in situ or the noninvasive precancerous lesion is a squamous cell carcinoma in situ like lesion. In various embodiments, the early-stage skin cancer in situ or the noninvasive precancerous lesion is a cutaneous squamous cell carcinoma. In a particular embodiment of the herein provided methods, the subject is human. In certain embodiments of said methods, the methods further comprise treating the subject with at least one other treatment regime selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, photodynamic therapy, electrocautery, laser therapy, cryosurgery, and surgery. In an embodiment of the herein provided methods, the combination of the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor is administered concurrently. In another embodiment, the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor are each administered individually in either order. In another embodiment, the method comprises a single administration of the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor.

[0024] In some embodiments of the herein provided methods, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of from 0.1 wt.% to 5 wt.% of the pharmaceutical composition. In certain embodiments, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of from 2 wt.% to 5 wt.% of the pharmaceutical composition. In some embodiments, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of from 0.1 wt.% to 0.5 wt.% of the pharmaceutical composition. In some embodiments, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of from 0.1 wt.% to 2 wt.% of the pharmaceutical composition. In some embodiments, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of from 0.5 wt.% to 2 wt.% of the pharmaceutical composition. In some embodiments, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of from 0.5 wt.% to 5 wt.% of the pharmaceutical composition.P-637213-PC

[0025] In another aspect, the present invention provides a method for inducing regression or achieving clearance of an early-stage skin cancer in situ or a noninvasive precancerous lesion in a subject in need thereof, the method comprising topically administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor. In some embodiments of the herein provided methods, the tyrosine kinase inhibitor is a Src family tyrosine kinase (SFK) inhibitor. In a particular embodiment of the herein provided methods, the tyrosine kinase inhibitor is selected from, but is not limited to, the group consisting of Dasatinib, Ponatinib, Saracatinib, Bosutinib, Rebastinib, Masitinib, Tirbanibulin, Bafetinib, SU6656 and Elzovanitinib, and the PI3K / mTOR inhibitor is selected from, but is not limited to, the group consisting of bimiralisib (PQR309), Umbralisib, Buparlisib, PIK-75 hydrochloride, AZD 6482, VS-5584, Pilaralisib, SAR-260301, Acalisib, Copanlisib, Pictilisib, Dactolisib, Inavolisib, Idelalisib, Duvelisib, Omipalisib, Taselisib and Voxtalisib. In particular embodiments, the tyrosine kinase inhibitor is dasatinib and the PI3K / mTOR inhibitor is bimiralisib (PQR309). In some embodiments, the tyrosine kinase inhibitor is dasatinib and the PI3K / mTOR inhibitor is buparlisib. In certain embodiments of the herein provided methods, the early-stage skin cancer in situ or the noninvasive precancerous lesion is actinic keratosis. In an embodiment of said methods, the early-stage skin cancer in situ or the noninvasive precancerous lesion is a squamous cell carcinoma in situ like lesion. In some embodiments of said methods, the early-stage skin cancer in situ or the noninvasive precancerous lesion is cutaneous squamous cell carcinoma. In a particular embodiment of said methods, the subject is human. In certain embodiments of said methods, the methods further comprise treating the subject with at least one other treatment regime selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, photodynamic therapy, electrocautery, laser therapy, cryosurgery, and surgery. In another embodiment, the method comprises a single administration of the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor.

[0026] In some embodiments of the herein provided methods, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of from 0.1 wt.% to 5 wt.% of the pharmaceutical composition. In some embodiments, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of from 2 wt.% to 5 wt.% of the pharmaceutical composition. In certain embodiments, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of fromP-637213-PC 0.1 wt.% to 0.5 wt.% of the pharmaceutical composition. In some embodiments, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of from 0.1 wt.% to 2 wt.% of the pharmaceutical composition. In some embodiments, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of from 0.5 wt.% to 2 wt.% of the pharmaceutical composition. In some embodiments, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of from 0.5 wt.% to 5 wt.% of the pharmaceutical composition.

[0027] In one aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor, and a pharmaceutically acceptable carrier. In an embodiment of said pharmaceutical composition, the tyrosine kinase inhibitor is a Src family tyrosine kinase (SFK) inhibitor. In some embodiments of the herein provided pharmaceutical compositions, the tyrosine kinase inhibitor is selected from, but is not limited to, the group consisting of Dasatinib, Ponatinib, Saracatinib, Bosutinib, Rebastinib, Masitinib, Tirbanibulin, Bafetinib, SU6656 and Elzovanitinib, and the PI3K / mTOR inhibitor is selected from the group consisting of bimiralisib (PQR309), Umbralisib, Buparlisib, PIK-75 hydrochloride, AZD 6482, VS-5584, Pilaralisib, SAR-260301, Acalisib, Copanlisib, Pictilisib, Dactolisib, Inavolisib, Idelalisib, Duvelisib, Omipalisib, Taselisib and Voxtalisib. In a particular embodiment, the tyrosine kinase inhibitor is dasatinib and the PI3K / mTOR inhibitor is bimiralisib (PQR309). In some embodiments, the tyrosine kinase inhibitor is dasatinib and the PI3K / mTOR inhibitor is buparlisib. In various embodiments of said pharmaceutical composition, the pharmaceutical composition is formulated as an ointment, gel, solution, cream, lotion, foam, powder, paste, stick, spray, spray-on patch, or a transdermal patch. In some embodiments of the herein provided pharmaceutical compositions, the pharmaceutical composition is formulated in liposomes. In some embodiments, the pharmaceutical composition has a therapeutically effective amount of from 0.1 wt.% to 5 wt.% of the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor in the composition. In some embodiments, the pharmaceutical composition has a therapeutically effective amount of from 2 wt.% to 5 wt.% of the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor in the pharmaceutical composition. In some embodiments, the pharmaceutical composition has a therapeutically effective amount of from 0.1 wt.% to 0.5 wt.% of the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor in the pharmaceutical composition. In some embodiments, the pharmaceutical composition has a therapeuticallyP-637213-PC effective amount of from 0.5 wt.% to 5 wt.% of the tyrosine kinase inhibitor and / or the PI3K / mTOR inhibitor in the composition. In some embodiments, the pharmaceutical composition has a therapeutically effective amount of from 0.5 wt.% to 2 wt.% of the tyrosine kinase inhibitor and / or the PI3K / mTOR inhibitor in the composition. In some embodiments, the pharmaceutical composition has a therapeutically effective amount of from 0.1 wt.% to 2 wt.% of the tyrosine kinase inhibitor and / or the PI3K / mTOR inhibitor in the composition. In an embodiment, the pharmaceutical composition comprising the therapeutically effective amount of a combination of the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor, is for treating an early-stage skin cancer in situ or a noninvasive precancerous lesion in a subject in need thereof. In certain embodiments, the pharmaceutical composition comprising the therapeutically effective amount of a combination of the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor, is for treating an invasive skin cancer lesion in a subject in need thereof.

[0028] In another aspect, the present invention provides a spray-on patch for treating an early- stage skin cancer in situ or a noninvasive precancerous lesion, the spray-on patch comprising a pharmaceutical composition comprising a therapeutically effective amount of a combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor. In some embodiments of the herein provided spray-on patch, the tyrosine kinase inhibitor is a Src family tyrosine kinase (SFK) inhibitor. In an embodiment of said spray-on patch, the tyrosine kinase inhibitor is selected from, but is not limited to, the group consisting of Dasatinib, Ponatinib, Saracatinib, Bosutinib, Rebastinib, Masitinib, Tirbanibulin, Bafetinib, SU6656 and Elzovanitinib and the PI3K / mTOR inhibitor is selected from, but is not limited to, the group consisting of bimiralisib (PQR309), Umbralisib, Buparlisib, PIK- 75 hydrochloride, AZD 6482, VS-5584, Pilaralisib, SAR-260301, Acalisib, Copanlisib, Pictilisib, Dactolisib, Inavolisib, Idelalisib, Duvelisib, Omipalisib, Taselisib and Voxtalisib. In some embodiments, the tyrosine kinase inhibitor is dasatinib and the PI3K / mTOR inhibitor is bimiralisib (PQR309). In some embodiments, the tyrosine kinase inhibitor is dasatinib and the PI3K / mTOR inhibitor is buparlisib. In various embodiments of the herein provided spray-on patch, the early- stage skin cancer in situ or the noninvasive precancerous lesion is actinic keratosis. In some embodiments of the spray-on patch, the early-stage skin cancer in situ or the noninvasive precancerous lesion is a squamous cell carcinoma in situ like lesion. In certain embodiments of the spray-on patch, the early-stage skin cancer in situ or the noninvasive precancerous lesion is cutaneous squamous cell carcinoma. In a particular embodiment, the subject is human.P-637213-PC

[0029] In some embodiments of the spray-on patch, the tyrosine kinase and the PI3K / mTOR inhibitors are present in a therapeutically effective amount of from 0.1 wt.% to 5 wt.% of the pharmaceutical composition in the spray-on patch. In some embodiments, the tyrosine kinase and the PI3K / mTOR inhibitor are present in a therapeutically effective amount of from 2 wt.% to 5 wt.% of the pharmaceutical composition in the spray-on patch. In some embodiments, the tyrosine kinase and the PI3K / mTOR inhibitors are present in a therapeutically effective amount of from 0.1 wt.% to 0.5 wt.% of the pharmaceutical composition in the spray-on patch. In some embodiments, the tyrosine kinase and the PI3K / mTOR inhibitors are present in a therapeutically effective amount of from 0.1 wt.% to 2 wt.% of the pharmaceutical composition in the spray-on patch. In some embodiments, the tyrosine kinase and the PI3K / mTOR inhibitors are present in a therapeutically effective amount of from 0.5 wt.% to 2 wt.% of the pharmaceutical composition in the spray-on patch. In some embodiments, the tyrosine kinase and the PI3K / mTOR inhibitors are present in a therapeutically effective amount of from 0.5 wt.% to 5 wt.% of the pharmaceutical composition in the spray-on patch.

[0030] In a particular embodiment, the spray-on patch is formulated as a liquid spray (e.g., using MedSpray® technology by MedPharm, Durham, NC) that creates a thin clear film after administration by spraying, i.e., a “patch,” or small molecule “depot” on the skin or a tissue surface having an early-stage skin cancer in situ or noninvasive precancerous lesion, wherein the liquid spray comprises the tyrosine kinase and the PI3K / mTOR inhibitors as the active pharmaceutical ingredients (APIs), also called therapeutic agents herein. The MedSpray® technology thermodynamically optimizes maximum permeation and penetration of the therapeutic agents through the skin and tissue, thereby providing long-term dosing of the herein provided small molecule therapeutic agents, i.e., the combination of the tyrosine kinase and the PI3K / mTOR inhibitors. In an embodiment, the spray-on patch adheres to the skin or tissue from three days up to one week after administration and delivers a sustained release of the tyrosine kinase and the PI3K / mTOR inhibitors through the skin and tissue. The spray-on patch is well-tolerated and cosmetically acceptable to patients.

[0031] In still another aspect, the present invention provides a transdermal patch for treating an early-stage skin cancer in situ or a noninvasive precancerous lesion, the transdermal patch comprising a pharmaceutical composition comprising a therapeutically effective amount of a combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor. In some embodiments ofP-637213-PC the herein provided transdermal patch, the tyrosine kinase inhibitor is a Src family tyrosine kinase (SFK) inhibitor. In an embodiment of said transdermal patch, the tyrosine kinase inhibitor is selected from, but is not limited to, the group consisting of Dasatinib, Ponatinib, Saracatinib, Bosutinib, Rebastinib, Masitinib, Tirbanibulin, Bafetinib, SU6656 and Elzovanitinib and the PI3K / mTOR inhibitor is selected from, but is not limited to, the group consisting of bimiralisib (PQR309), Umbralisib, Buparlisib, PIK-75 hydrochloride, AZD 6482, VS-5584, Pilaralisib, SAR- 260301, Acalisib, Copanlisib, Pictilisib, Dactolisib, Inavolisib, Idelalisib, Duvelisib, Omipalisib, Taselisib and Voxtalisib. In some embodiments, the tyrosine kinase inhibitor is dasatinib and the PI3K / mTOR inhibitor is bimiralisib (PQR309). In some embodiments, the tyrosine kinase inhibitor is dasatinib and the PI3K / mTOR inhibitor is buparlisib. In various embodiments of the herein provided transdermal patch, the early-stage skin cancer in situ or the noninvasive precancerous lesion is actinic keratosis. In some embodiments of the transdermal patch, the early- stage skin cancer in situ or the noninvasive precancerous lesion is a squamous cell carcinoma in situ like lesion. In certain embodiments of the transdermal patch, the early-stage skin cancer in situ or the noninvasive precancerous lesion is cutaneous squamous cell carcinoma. In a particular embodiment, the subject is human.

[0032] In some embodiments of the transdermal patch, the tyrosine kinase and the PI3K / mTOR inhibitors are present in a therapeutically effective amount of from 0.1 wt.% to 5 wt.% of the pharmaceutical composition in the transdermal patch. In some embodiments, the tyrosine kinase and the PI3K / mTOR inhibitor are present in a therapeutically effective amount of from 2 wt.% to 5 wt.% of the pharmaceutical composition in the transdermal patch. In some embodiments, the tyrosine kinase and the PI3K / mTOR inhibitors are present in a therapeutically effective amount of from 0.1 wt.% to 0.5 wt.% of the pharmaceutical composition in the transdermal patch. In some embodiments, the tyrosine kinase and the PI3K / mTOR inhibitors are present in a therapeutically effective amount of from 0.1 wt.% to 2 wt.% of the pharmaceutical composition in the transdermal patch. In some embodiments, the tyrosine kinase and the PI3K / mTOR inhibitors are present in a therapeutically effective amount of from 0.5 wt.% to 2 wt.% of the pharmaceutical composition in the transdermal patch. In some embodiments, the tyrosine kinase and the PI3K / mTOR inhibitors are present in a therapeutically effective amount of from 0.5 wt.% to 5 wt.% of the pharmaceutical composition in the transdermal patch.P-637213-PC

[0033] In yet another aspect, the present invention provides a method for treating an invasive skin cancer lesion in a subject in need thereof, the method comprising topically administering to the subject a therapeutically effective amount of a combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor. In an embodiment of the herein provided method, the tyrosine kinase inhibitor is a Src family tyrosine kinase (SFK) inhibitor. In a particular embodiment of said methods, the tyrosine kinase inhibitor is selected from, but is not limited to, the group consisting of Dasatinib, Ponatinib, Saracatinib, Bosutinib, Rebastinib, Masitinib, Tirbanibulin, Bafetinib, SU6656 and Elzovanitinib and the PI3K / mTOR inhibitor is selected from, but is not limited to, the group consisting of bimiralisib (PQR309), Umbralisib, Buparlisib, PIK-75 hydrochloride, AZD 6482, VS-5584, Pilaralisib, SAR-260301, Acalisib, Copanlisib, Pictilisib, Dactolisib, Inavolisib, Idelalisib, Duvelisib, Omipalisib, Taselisib and Voxtalisib. In particular embodiments, the tyrosine kinase inhibitor is dasatinib and the PI3K / mTOR inhibitor is bimiralisib (PQR309). In some embodiments, the tyrosine kinase inhibitor is dasatinib and the PI3K / mTOR inhibitor is buparlisib. In various embodiments of the herein provided methods, the invasive skin cancer lesion is a basal cell carcinoma. In some embodiments of said methods, the invasive skin cancer lesion is squamous cell carcinoma. In embodiments of the herein provided methods, the invasive skin cancer lesion is Merkel cell carcinoma. In certain embodiments of the herein provided methods, the subject is human. In some embodiments of said methods, the methods further comprise treating the subject with at least one other treatment regime selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, photodynamic therapy, electrocautery, laser therapy, cryosurgery, and surgery. In an embodiment of the herein provided methods, the combination of the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor is administered concurrently. In another embodiment, the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor are each administered individually in either order. In another embodiment, the method comprises a single administration of the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor.

[0034] In some embodiments of the herein provided methods, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of from 0.1 wt.% to 5 wt.% of the pharmaceutical composition. In some embodiments, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of from 0.5 wt.% to 5 wt.% of the pharmaceutical composition. In an embodiment, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of from 0.5P-637213-PC wt.% to 2 wt.% of the pharmaceutical composition. In some embodiments, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of from 0.1 wt.% to 2 wt.% of the pharmaceutical composition.

[0035] In another aspect, the present invention provides a method for inducing regression or remission of an invasive skin cancer lesion in a subject in need thereof, the method comprising topically administering to the subject a therapeutically effective amount of a combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor. In some embodiments of the herein provided methods, the tyrosine kinase inhibitor is a Src family tyrosine kinase (SFK) inhibitor. In an embodiment of the herein provided methods, the tyrosine kinase inhibitor is selected from, but is not limited to, the group consisting of Dasatinib, Ponatinib, Saracatinib, Bosutinib, Rebastinib, Masitinib, Tirbanibulin, Bafetinib, SU6656 and Elzovanitinib and the PI3K / mTOR inhibitor is selected from, but is not limited to, the group consisting of bimiralisib (PQR309), Umbralisib, Buparlisib, PIK-75 hydrochloride, AZD 6482, VS-5584, Pilaralisib, SAR-260301, Acalisib, Copanlisib, Pictilisib, Dactolisib, Inavolisib, Idelalisib, Duvelisib, Omipalisib, Taselisib and Voxtalisib. In a particular embodiment, the tyrosine kinase inhibitor is dasatinib and the PI3K / mTOR inhibitor is bimiralisib (PQR309). In some embodiments, the tyrosine kinase inhibitor is dasatinib and the PI3K / mTOR inhibitor is buparlisib. In some embodiments of said methods, the invasive skin cancer lesion is a basal cell carcinoma. In certain embodiments of the herein provided methods, the invasive skin cancer lesion is squamous cell carcinoma. In various embodiments of said methods, the invasive skin cancer lesion is Merkel cell carcinoma. In a particular embodiment of said methods, the subject is human. In some embodiments of said methods, the methods further comprise treating the subject with at least one other treatment regime selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, photodynamic therapy, electrocautery, laser therapy, cryosurgery, and surgery. In an embodiment of the herein provided methods, the combination of the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor is administered concurrently. In another embodiment, the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor are each administered individually in either order. In another embodiment, the method comprises a single administration of the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor.

[0036] In some embodiments of the herein provided methods, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of from 0.1P-637213-PC wt.% to 5 wt.% of the pharmaceutical composition. In some embodiments, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of from 2 wt.% to 5 wt.% of the pharmaceutical composition. In certain embodiments, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of from 0.1 wt.% to 0.5 wt.% of the pharmaceutical composition. In some embodiments, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of from 0.5 wt.% to 5 wt.% of the pharmaceutical composition. In some embodiments, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of from 0.1 wt.% to 2 wt.% of the pharmaceutical composition. In some embodiments, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of from 0.5 wt.% to 2 wt.% of the pharmaceutical composition.

[0037] Unless the context clearly requires otherwise, throughout the description and the claims, the words “comprise,” “comprising,” and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of “including, but not limited to.” Words using the singular or plural number also include the plural or singular number, respectively. Additionally, the words “herein,” “above,” and “below” and words of similar import, when used in this application, shall refer to this application as a whole and not to any particular portions of this application. As used herein, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. “And” as used herein is interchangeably used with “or” unless expressly stated otherwise.

[0038] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and / or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting. Each literature reference or other citation referred to herein is incorporated herein by reference in its entirety.

[0039] In the description presented herein, each of the steps of the invention and variations thereof are described. This description is not intended to be limiting and changes in the components, sequence of steps, and other variations would be understood to be within the scope of the presentP-637213-PC invention.

[0040] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments unless the embodiment is inoperative without those elements.

[0041] Throughout this application, various embodiments of the present disclosure may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0042] Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases “ranging / ranges between” a first indicate number and a second indicate number and “ranging / ranges from” a first indicate number “to” a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.

[0043] When values are expressed as approximations, by use of the antecedent "about," it is understood that the particular value forms another embodiment. All ranges are inclusive and combinable. In one embodiment, the term “about” refers to a deviance of between 0.1-5% from the indicated number or range of numbers. In another embodiment, the term “about” refers to a deviance of between 1-10% from the indicated number or range of numbers. In another embodiment, the term “about” refers to a deviance of up to 20% from the indicated number or range of numbers. In one embodiment, the term “about” refers to a deviance of ± 10% from the indicated number or range of numbers. In another embodiment, the term “about” refers to a deviance of ± 5% from the indicated number or range of numbers.P-637213-PC Therapeutic Methods

[0044] As used herein, the terms “treat,” “treatment” or “therapy” (as well as different forms thereof) refer to therapeutic treatment, including prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change associated with a disease or condition. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of the extent of a disease or condition, stabilization of a disease or condition (i.e., where the disease or condition does not worsen), delay or slowing of the progression of a disease or condition, amelioration or palliation of the disease or condition, and remission (whether partial or total) of the disease or condition, whether detectable or undetectable. Those in need of treatment include those already with the disease or condition as well as those prone to having the disease or condition or those in which the disease or condition is to be prevented. In a particular embodiment, the disease or condition is early-stage UV-induced skin cancers, precancerous lesions, including but not limited to, actinic keratoses (AKs) and squamous cell carcinoma in situ (SCCIS).

[0045] The terms “subject,” “individual,” and “patient” are used interchangeably herein, and refer to human or non-human animals to whom treatment with a composition or formulation in accordance with the present disclosure is provided. The terms "non-human animals" and "non- human mammals" are used interchangeably herein and include all vertebrates, e.g., mammals, such as non-human primates (e.g., higher primates), sheep, dog, rodent (e.g. mouse or rat), guinea pig, goat, pig, cat, rabbits, cows, horses, or non-mammals such as reptiles, amphibians, chickens, and turkeys. The compositions described herein can be used to treat any suitable mammal, including primates, such as monkeys and humans, horses, cows, cats, dogs, rabbits, and rodents such as rats and mice. In one embodiment, the mammal to be treated is human. The human can be any human of any age. In one embodiment, the human is an adult. In another embodiment, the human is a child, though the incidence of precancerous lesions and skin cancers is very low in this group. The human can be male, female, pregnant, middle-aged, adolescent, or elderly.

[0046] In one aspect, the present invention provides a method for treating an early-stage skin cancer in situ or a noninvasive precancerous lesion in a subject in need thereof, the method comprising topically administering to the subject a therapeutically effective amount of a combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor. In an embodiment of the method, the tyrosine kinase inhibitor is a Src family tyrosine kinase (SFK) inhibitor. In someP-637213-PC embodiments, the tyrosine kinase inhibitor is selected from, but is not limited to, the group consisting of Dasatinib, Ponatinib, Saracatinib, Bosutinib, Rebastinib, Masitinib, Tirbanibulin, Bafetinib, SU6656 and Elzovanitinib and the PI3K / mTOR inhibitor is selected from, but is not limited to, the group consisting of bimiralisib (PQR309), Umbralisib, Buparlisib, PIK-75 hydrochloride, AZD 6482, VS-5584, Pilaralisib, SAR-260301, Acalisib, Copanlisib, Pictilisib, Dactolisib, Inavolisib, Idelalisib, Duvelisib, Omipalisib, Taselisib and Voxtalisib. In some embodiments, the tyrosine kinase inhibitor is dasatinib and the PI3K / mTOR inhibitor is bimiralisib (PQR309). In some embodiments, the tyrosine kinase inhibitor is dasatinib and the PI3K / mTOR inhibitor is buparlisib. In an embodiment, the early-stage skin cancer in situ or the noninvasive precancerous lesion is actinic keratosis. In some embodiments, the early-stage skin cancer in situ or the noninvasive precancerous lesion is a squamous cell carcinoma in situ like lesion. In various embodiments, the early-stage skin cancer in situ or the noninvasive precancerous lesion is associated with cutaneous squamous cell carcinoma. In a particular embodiment, of the herein provided methods, the subject is human. In certain embodiments of said methods, the methods further comprise treating the subject with at least one other treatment regime selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, photodynamic therapy, electrocautery, laser therapy, cryosurgery, and surgery. In an embodiment of the herein provided methods, the combination of the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor is administered concurrently. In another embodiment, the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor are each administered individually in either order. In another embodiment, the method comprises a single administration of the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor.

[0047] In some embodiments of the herein provided methods, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of from 0.1 wt.% to 5 wt.% of the pharmaceutical composition. In some embodiments, the tyrosine kinase and the PI3K / mTOR inhibitor are each administered in a therapeutically effective amount of from 2 wt.% to 5 wt.% of the pharmaceutical composition. In an embodiment, the tyrosine kinase and the PI3K / mTOR inhibitor are each administered in a therapeutically effective amount of from 0.1 wt.% to 0.5 wt.% of the pharmaceutical composition. In some embodiments, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of from 0.5 wt.% to 5 wt.% of the pharmaceutical composition. In some embodiments, the tyrosine kinaseP-637213-PC and the PI3K / mTOR inhibitor are each administered in a therapeutically effective amount of from 0.1 wt.% to 2 wt.% of the pharmaceutical composition. In an embodiment, the tyrosine kinase and the PI3K / mTOR inhibitor are each administered in a therapeutically effective amount of from 0.5 wt.% to 2 wt.% of the pharmaceutical composition.

[0048] In another aspect, the present invention provides a method for inducing regression or achieving clearance of an early-stage skin cancer in situ or a noninvasive precancerous lesion in a subject in need thereof, the method comprising topically administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor. In some embodiments of the herein provided methods, the tyrosine kinase inhibitor is a Src family tyrosine kinase (SFK) inhibitor. In a particular embodiment, of the herein provided methods, the tyrosine kinase inhibitor is selected from, but is not limited to, the group consisting of Dasatinib, Ponatinib, Saracatinib, Bosutinib, Rebastinib, Masitinib, Tirbanibulin, Bafetinib, SU6656 and Elzovanitinib and the PI3K / mTOR inhibitor is selected from, but is not limited to, the group consisting of bimiralisib (PQR309), Umbralisib, Buparlisib, PIK-75 hydrochloride, AZD 6482, VS-5584, Pilaralisib, SAR-260301, Acalisib, Copanlisib, Pictilisib, Dactolisib, Inavolisib, Idelalisib, Duvelisib, Omipalisib, Taselisib and Voxtalisib. In particular embodiments, the tyrosine kinase inhibitor is dasatinib and the PI3K / mTOR inhibitor is bimiralisib (PQR309). In some embodiments, the tyrosine kinase inhibitor is dasatinib and the PI3K / mTOR inhibitor is buparlisib. In certain embodiments of the herein provided methods, the early-stage skin cancer in situ or the noninvasive precancerous lesion is actinic keratosis. In an embodiment of said methods, the early-stage skin cancer in situ or the noninvasive precancerous lesion is a squamous cell carcinoma in situ like lesion. In some embodiments of said methods, the early-stage skin cancer in situ or the noninvasive precancerous lesion is associated with cutaneous squamous cell carcinoma. In a particular embodiment of said methods, the subject is human. In certain embodiments of said methods, the methods further comprise treating the subject with at least one other treatment regime selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, photodynamic therapy, electrocautery, laser therapy, cryosurgery, and surgery. In an embodiment of the herein provided methods, the combination of the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor is administered concurrently. In another embodiment, the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor are each administered individually in either order.P-637213-PC

[0049] In some embodiments of the herein provided methods, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of from 0.1 wt.% to 5 wt.% of the pharmaceutical composition. In some embodiments, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of from 2 wt.% to 5 wt.% of the pharmaceutical composition. In certain embodiments, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of from 0.1 wt.% to 0.5 wt.% of the pharmaceutical composition. In some embodiments, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of from 0.5 wt.% to 5 wt.% of the pharmaceutical composition. In some embodiments, the tyrosine kinase and the PI3K / mTOR inhibitor are each administered in a therapeutically effective amount of from 0.1 wt.% to 2 wt.% of the pharmaceutical composition. In an embodiment, the tyrosine kinase and the PI3K / mTOR inhibitor are each administered in a therapeutically effective amount of from 0.5 wt.% to 2 wt.% of the pharmaceutical composition.

[0050] It is further envisioned that the combination of a tyrosine kinase inhibitor, such as a Src family tyrosine kinase (SFK) inhibitor, and a PI3K / mTOR inhibitor will treat invasive skin lesions and skin cancers. Thus, in yet another aspect, the present invention provides a method for treating an invasive skin cancer lesion in a subject in need thereof, the method comprising topically administering to the subject a therapeutically effective amount of a combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor. In embodiments of the herein provided method, the tyrosine kinase inhibitor is a Src family tyrosine kinase (SFK) inhibitor. In a particular embodiment of said methods, the tyrosine kinase inhibitor is selected from, but is not limited to, the group consisting of Dasatinib, Ponatinib, Saracatinib, Bosutinib, Rebastinib, Masitinib, Tirbanibulin, Bafetinib, SU6656 and Elzovanitinib and the PI3K / mTOR inhibitor is selected from, but is not limited to, the group consisting of bimiralisib (PQR309), Umbralisib, Buparlisib, PIK-75 hydrochloride, AZD 6482, VS-5584, Pilaralisib, SAR-260301, Acalisib, Copanlisib, Pictilisib, Dactolisib, Inavolisib, Idelalisib, Duvelisib, Omipalisib, Taselisib and Voxtalisib. In particular embodiments, the tyrosine kinase inhibitor is dasatinib and the PI3K / mTOR inhibitor is bimiralisib (PQR309). In some embodiments, the tyrosine kinase inhibitor is dasatinib and the PI3K / mTOR inhibitor is buparlisib. In various embodiments of the herein provided methods, the invasive skin cancer lesion is a basal cell carcinoma. In some embodiments of said methods, the invasive skin cancer lesion is squamous cell carcinoma. In embodiments of the herein provided methods, theP-637213-PC invasive skin cancer lesion is Merkel cell carcinoma. In certain embodiments of the herein provided methods, the subject is human. In some embodiments of said methods, the methods further comprise treating the subject with at least one other treatment regime selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, photodynamic therapy, electrocautery, laser therapy, cryosurgery, and surgery. In embodiments of the herein provided methods, the combination of the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor is administered concurrently. In another embodiment, the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor are each administered individually in either order.

[0051] In some embodiments of the herein provided methods, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of from 0.1 wt.% to 5 wt.% of the pharmaceutical composition. In some embodiments, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of from 2 wt.% to 5 wt.% of the pharmaceutical composition. In an embodiment, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of from 0.1 wt.% to 0.5 wt.% of the pharmaceutical composition. In some embodiments, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of from 0.5 wt.% to 5 wt.% of the pharmaceutical composition. In some embodiments, the tyrosine kinase and the PI3K / mTOR inhibitor are each administered in a therapeutically effective amount of from 0.1 wt.% to 2 wt.% of the pharmaceutical composition. In an embodiment, the tyrosine kinase and the PI3K / mTOR inhibitor are each administered in a therapeutically effective amount of from 0.5 wt.% to 2 wt.% of the pharmaceutical composition.

[0052] In another aspect, the present invention provides a method for inducing regression or remission of an invasive skin cancer lesion in a subject in need thereof, the method comprising topically administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor. In some embodiments of the herein provided method, the tyrosine kinase inhibitor is a Src family tyrosine kinase (SFK) inhibitor. In an embodiment of the herein provided methods, the tyrosine kinase inhibitor is selected from, but is not limited to, the group consisting of Dasatinib, Ponatinib, Saracatinib, Bosutinib, Rebastinib, Masitinib, Tirbanibulin, Bafetinib, SU6656 and Elzovanitinib and the PI3K / mTOR inhibitor is selected from, but is not limited to, the group consisting of bimiralisib (PQR309), Umbralisib, Buparlisib, PIK-75 hydrochloride, AZD 6482, VS-5584,P-637213-PC Pilaralisib, SAR-260301, Acalisib, Copanlisib, Pictilisib, Dactolisib, Inavolisib, Idelalisib, Duvelisib, Omipalisib, Taselisib and Voxtalisib. In a particular embodiment, the tyrosine kinase inhibitor is dasatinib and the PI3K / mTOR inhibitor is bimiralisib (PQR309). In some embodiments, the tyrosine kinase inhibitor is dasatinib and the PI3K / mTOR inhibitor is buparlisib. In some embodiments of said methods, the invasive skin cancer lesion is a basal cell carcinoma. In certain embodiments of the herein provided methods, the invasive skin cancer lesion is squamous cell carcinoma. In various embodiments of said methods, the invasive skin cancer lesion is Merkel cell carcinoma. In a particular embodiment of said methods, the subject is human. In some embodiments of said methods, the methods further comprise treating the subject with at least one other treatment regime selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, photodynamic therapy, electrocautery, laser therapy, cryosurgery, and surgery.

[0053] In some embodiments of the herein provided methods, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of from 0.1 wt.% to 5 wt.% of the pharmaceutical composition. In some embodiments, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of from 2 wt.% to 5 wt.% of the pharmaceutical composition. In certain embodiments, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of from 0.1 wt.% to 0.5 wt.% of the pharmaceutical composition. In some embodiments, the tyrosine kinase and the PI3K / mTOR inhibitors are each administered in a therapeutically effective amount of from 0.5 wt.% to 5 wt.% of the pharmaceutical composition. In some embodiments, the tyrosine kinase and the PI3K / mTOR inhibitor are each administered in a therapeutically effective amount of from 0.1 wt.% to 2 wt.% of the pharmaceutical composition. In an embodiment, the tyrosine kinase and the PI3K / mTOR inhibitor are each administered in a therapeutically effective amount of from 0.5 wt.% to 2 wt.% of the pharmaceutical composition. Pharmaceutical Compositions

[0054] The combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor described and administered according to the methods provided herein are formulated as pharmaceutical compositions comprising therapeutic agents, i.e., at least one tyrosine kinase inhibitor, such as a Src family tyrosine kinase inhibitor (“SFK inhibitor”), and at least one PI3K / mTOR inhibitor, respectively, and one or more pharmaceutically acceptable carriers. “Pharmaceutically acceptable carriers” include any excipient which is nontoxic to the cell or mammal being exposed thereto atP-637213-PC the dosages and concentrations employed. The pharmaceutical composition may include one or more of each respective therapeutic agent.

[0055] Thus, as used herein, “pharmaceutically acceptable carrier” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference. Examples of such carriers or diluents include, but are not limited to, water, saline, finger's solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles such as fixed oils may also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the herein described pharmaceutical compositions is contemplated. Supplementary active compounds can also be incorporated into the pharmaceutical compositions.

[0056] Carriers may be any of those conventionally used, as described above, and are limited only by chemical-physical considerations, such as solubility and lack of reactivity with the compound of the invention, and by the route of administration. The choice of carrier will be determined by the particular method used to administer the pharmaceutical composition. Some examples of suitable carriers include lactose, glucose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water and methylcellulose. The formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents, surfactants, emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; flavoring agents, colorants, buffering agents (e.g., acetates, citrates or phosphates), disintegrating agents, moistening agents, antibacterial agents, antioxidants (e.g., ascorbic acid or sodium bisulfite), chelating agents (e.g., ethylenediaminetetraacetic acid), and agents for the adjustment of tonicity such as sodium chloride. Other pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.P-637213-PC

[0057] Pharmaceutical compositions suitable for injectable use may include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include, without limitation, physiological saline, bacteriostatic water, Cremophor EL.TM. (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). The composition should be sterile and should be fluid to the extent that easy syringeability exists. It should be stable under the conditions of manufacture and storage and be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0058] Sterile injectable solutions can be prepared by incorporating the active compounds (tyrosine kinase and PI3K / mTOR inhibitors, respectively) in the required amount to produce a therapeutic effect in an appropriate solvent with one or a combination of ingredients enumerated above, as appropriate, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0059] The pharmaceutical compositions and formulations comprising a therapeutically effective amount of a combination of a tyrosine kinase inhibitor, such as a Src family tyrosine kinase inhibitor (“SFK inhibitor”) and a PI3K / mTOR inhibitor, as respectively described herein, may be administered alone or with other biologically-active agents. It is desirable to administer theP-637213-PC therapeutic locally to the area in need of treatment; this may be achieved by, for example, and not by way of limitation, topical application, local infusion during surgery, by injection, by means of a catheter, or by means of an implant or a patch. In an embodiment, the patch is a transdermal patch.

[0060] In some embodiments, the respective transdermal patches comprise a pharmaceutical composition comprising either the tyrosine kinase inhibitor or the PI3K / mTOR inhibitor present in a therapeutically effective amount of from 0.1 wt.% to 5 wt.% of the pharmaceutical composition. In some embodiments, the transdermal patch comprises a pharmaceutical composition comprising both the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor, wherein each of the tyrosine kinase and the PI3K / mTOR inhibitors are present in a therapeutically effective amount of from 0.1 wt.% to 5 wt.% of the pharmaceutical composition. In some embodiments, the transdermal patch comprises a pharmaceutical composition comprising both the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor, wherein each of the tyrosine kinase and the PI3K / mTOR inhibitors are present in a therapeutically effective amount of from 0.1 wt.% to 0.5 wt.% of the pharmaceutical composition. In some embodiments, the transdermal patch comprises a pharmaceutical composition comprising both the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor, wherein each of the tyrosine kinase and the PI3K / mTOR inhibitors are present in a therapeutically effective amount of from 2 wt.% to 5 wt.% of the pharmaceutical composition. In some embodiments, the transdermal patch comprises a pharmaceutical composition comprising both the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor, wherein each of the tyrosine kinase and the PI3K / mTOR inhibitors are present in a therapeutically effective amount of from 0.1 wt.% to 0.5 wt.% of the pharmaceutical composition. In some embodiments, the transdermal patch comprises a pharmaceutical composition comprising both the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor, wherein each of the tyrosine kinase and the PI3K / mTOR inhibitors are present in a therapeutically effective amount of from 0.5 wt.% to 5 wt.% of the pharmaceutical composition. In some embodiments, the transdermal patch comprises a pharmaceutical composition comprising both the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor, wherein each of the tyrosine kinase and the PI3K / mTOR inhibitors are present in a therapeutically effective amount of from 0.1 wt.% to 2 wt.% of the pharmaceutical composition. In some embodiments, the transdermal patch comprises a pharmaceutical composition comprising both the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor, wherein each of the tyrosine kinase and the PI3K / mTORP-637213-PC inhibitors are present in a therapeutically effective amount of from 0.5 wt.% to 2 wt.% of the pharmaceutical composition.

[0061] Moreover, “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem complications commensurate with a reasonable benefit / risk ratio. The term “pharmaceutically acceptable” also includes those carriers approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals and, more particularly, in humans.

[0062] In one aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor, and a pharmaceutically acceptable carrier. In an embodiment of said pharmaceutical composition, the tyrosine kinase inhibitor is a Src family tyrosine kinase (SFK) inhibitor. In some embodiments of the herein provided pharmaceutical compositions, the tyrosine kinase inhibitor is selected from, but is not limited to, the group consisting of Dasatinib, Ponatinib, Saracatinib, Bosutinib, Rebastinib, Masitinib, Tirbanibulin, Bafetinib, SU6656 and Elzovanitinib and the PI3K / mTOR inhibitor is selected from the group consisting of bimiralisib (PQR309), Umbralisib, Buparlisib, PIK-75 hydrochloride, AZD 6482, VS-5584, Pilaralisib, SAR-260301, Acalisib, Copanlisib, Pictilisib, Dactolisib, Inavolisib, Idelalisib, Duvelisib, Omipalisib, Taselisib and Voxtalisib. In a particular embodiment, the tyrosine kinase inhibitor is dasatinib and the PI3K / mTOR inhibitor is bimiralisib (PQR309). In some embodiments, the tyrosine kinase inhibitor is dasatinib and the PI3K / mTOR inhibitor is buparlisib. In various embodiment of said pharmaceutical composition, the pharmaceutical composition is formulated as an ointment, gel, solution, cream, lotion, foam, powder, paste, stick, spray, spray-on patch, or a transdermal patch. In some embodiments, the spray-on patch is formulated as a liquid spray (using MedSpray® technology by MedPharm, Durham, NC) that creates a thin clear film after administration by spraying, i.e., a “patch,” or small molecule “depot” on the skin or a tissue surface having an early- stage skin cancer in situ or noninvasive precancerous lesion, wherein the liquid spray comprises the tyrosine kinase and the PI3K / mTOR inhibitors as the active pharmaceutical ingredients. The MedSpray® technology thermodynamically optimizes maximum permeation and penetration of the therapeutic agents through the skin and tissue, thereby providing a long-term dosing of theP-637213-PC herein provided small molecule therapeutic agents, i.e., the combination of the tyrosine kinase and the PI3K / mTOR inhibitors. In an embodiment, the spray-on patch adheres to the skin or tissue and delivers a sustained release of the tyrosine kinase and the PI3K / mTOR inhibitors through the skin and tissue from three days up to one week after administration. The spray-on patch is well-tolerated by and cosmetically acceptable to patients.

[0063] In some embodiments of the herein provided pharmaceutical compositions, the pharmaceutical composition is formulated in liposomes. Effective doses

[0064] Effective doses of the pharmaceutical compositions of the present invention, for treatment of the conditions or diseases described herein, vary depending upon many different factors, including means of administration, target site, physiological state of the patient, whether the patient is human or an animal, other medications administered, and whether treatment is prophylactic or therapeutic. Usually, the patient is a human, but non-human mammals including transgenic mammals and genetically engineered mice can also be treated. Treatment dosages may be titrated using routine methods known to those of skill in the art to optimize safety and efficacy. The pharmaceutical compositions of the invention thus may include a “therapeutically effective amount.” A “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of a molecule, therapeutic agent, or pharmaceutical composition comprising a combination of therapeutic agents may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the molecule to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the molecule are outweighed by the therapeutically beneficial effects.

[0065] Furthermore, a skilled artisan would appreciate that the term “therapeutically effective amount” may encompass total amount of each active component of the pharmaceutical composition, i.e., a tyrosine kinase inhibitor, such as a Src family tyrosine kinase inhibitor (“SFK inhibitor”) and a PI3K / mTOR inhibitor, that is sufficient to show a meaningful patient benefit, i.e., treatment, healing, prevention or amelioration of the relevant medical condition, or an increase in rate of treatment, healing, prevention or amelioration of such conditions. When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that resultP-637213-PC in the therapeutic effect, whether administered in combination, serially or simultaneously, in particular a tyrosine kinase inhibitor, such as a Src family tyrosine kinase inhibitor (“SFK inhibitor”) and a PI3K / mTOR inhibitor.

[0066] The amount of a compound of the invention that will be effective in the treatment of a particular disorder or condition, such as non-invasive skin cancer lesions, also will depend on the nature of the disorder or condition and can be determined by standard clinical techniques. In addition, in vitro assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided according to the judgment of the practitioner and each patient’s circumstances. In one embodiment, the pharmaceutical composition comprising a therapeutically effective amount of a combination of a tyrosine kinase inhibitor, such as a Src family tyrosine kinase inhibitor (“SFK inhibitor”) and a PI3K / mTOR inhibitor is administered topically.

[0067] The compound(s) or composition(s) comprising the combination of a tyrosine kinase inhibitor, such as a Src family tyrosine kinase inhibitor (“SFK inhibitor”) and a PI3K / mTOR inhibitor of the invention may be administered only once, or it may be administered multiple times. For multiple dosages, the composition may be, for example, administered three times a day, twice a day, once a day, once every two days, twice a week, weekly, once every two weeks, or monthly. Spray-on Patch

[0068] In another aspect, provided herein is a spray-on patch (or small molecule scaffold / depot) for treating an early-stage skin cancer in situ or a noninvasive precancerous lesion, the spray-on patch comprising a pharmaceutical composition comprising a therapeutically effective amount of a combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor. In some embodiments of the herein provided spray-on patch, the tyrosine kinase inhibitor is a Src family tyrosine kinase (SFK) inhibitor. In an embodiment of said spray-on patch, the tyrosine kinase inhibitor is selected from, but is not limited to, the group consisting of Dasatinib, Ponatinib, Saracatinib, Bosutinib, Rebastinib, Masitinib, Tirbanibulin, Bafetinib, SU6656 and Elzovanitinib and the PI3K / mTOR inhibitor is selected from, but is not limited to, the group consisting of bimiralisib (PQR309), Umbralisib, Buparlisib, PIK-75 hydrochloride, AZD 6482, VS-5584, Pilaralisib, SAR-260301, Acalisib, Copanlisib, Pictilisib, Dactolisib, Inavolisib, Idelalisib, Duvelisib, Omipalisib, TaselisibP-637213-PC and Voxtalisib. In some embodiments, the tyrosine kinase inhibitor is dasatinib and the PI3K / mTOR inhibitor is bimiralisib (PQR309). In some embodiments, the tyrosine kinase inhibitor is dasatinib and the PI3K / mTOR inhibitor is buparlisib. In various embodiments of the herein provided spray-on patch, the early-stage skin cancer in situ or the noninvasive precancerous lesion is actinic keratosis. In some embodiments of the spray-on patch, the early-stage skin cancer in situ or the noninvasive precancerous lesion is a squamous cell carcinoma in situ like lesion. In certain embodiments of the spray-on patch, the early-stage skin cancer in situ or the noninvasive precancerous lesion is associated with cutaneous squamous cell carcinoma. In an embodiment of the spray-on patch, the early-stage skin cancer in situ or the noninvasive precancerous lesion is a keratinocyte hyperproliferation skin disorder, wherein the keratinocyte hyperproliferation skin disorder is psoriasis, lichen simplex chronicus, seborrheic keratoses, porokeratosis, lichen planus or verrucae (warts). In some embodiments, the spray-on patch is administered to treat an invasive skin cancer lesion and / or to induce regression or remission of an invasive skin cancer lesion, including but not limited to a basal cell carcinoma, a squamous cell carcinoma, or a Merkel cell carcinoma. In a particular embodiment, the subject is human.

[0069] In some embodiments, the spray-on patches have the tyrosine kinase and the PI3K / mTOR inhibitors each present in a therapeutically effective amount of from 0.1 wt.% to 5 wt.% of the pharmaceutical composition in the spray-on patch. In some embodiments, the spray-on patches have the tyrosine kinase and the PI3K / mTOR inhibitors each present in a therapeutically effective amount of from 2 wt.% to 5 wt.% of the pharmaceutical composition in the spray-on patch. In certain embodiments, the spray-on patches have the tyrosine kinase and the PI3K / mTOR inhibitors each present in a therapeutically effective amount of from 0.1 wt.% to 0.5 wt.% of the pharmaceutical composition in the spray-on patch. In some embodiments, the spray-on patches have the tyrosine kinase and the PI3K / mTOR inhibitors each present in a therapeutically effective amount of from 0.5 wt.% to 5 wt.% of the pharmaceutical composition in the spray-on patch. In some embodiments, the spray-on patches have the tyrosine kinase and the PI3K / mTOR inhibitors each present in a therapeutically effective amount of from 0.5 wt.% to 2 wt.% of the pharmaceutical composition in the spray-on patch. In certain embodiments, the spray-on patches have the tyrosine kinase and the PI3K / mTOR inhibitors each present in a therapeutically effective amount of from 0.1 wt.% to 2 wt.% of the pharmaceutical composition in the spray-on patch.P-637213-PC

[0070] In particular embodiments, the spray-on patch is formulated as a liquid spray (using MedSpray® technology by MedPharm, Durham, NC) that creates a thin clear film after administration by spraying, i.e., a “patch,” or small molecule “depot” on the skin or a tissue surface having an early-stage skin cancer in situ or noninvasive precancerous lesion, wherein the liquid spray comprises the tyrosine kinase and the PI3K / mTOR inhibitors as the therapeutic agents. The MedSpray® technology thermodynamically optimizes maximum permeation and penetration of the therapeutic agents through the skin and tissue, and thereby provides a long-term dosing, i.e., sustained release, of the herein provided small molecule therapeutic agents, i.e., the combination of the tyrosine kinase and the PI3K / mTOR inhibitors. In some embodiments, the spray-on patch adheres to the skin or tissue and delivers a sustained release of the tyrosine kinase and the PI3K / mTOR inhibitors from three days up to one week after administration. The spray-on patch is well-tolerated by and cosmetically acceptable to patients. Transdermal Patch

[0071] In still another aspect, the present invention provides a transdermal patch for treating an early-stage skin cancer in situ or a noninvasive precancerous lesion, the transdermal patch comprising a pharmaceutical composition comprising a therapeutically effective amount of a combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor. In some embodiments of the herein provided transdermal patch, the tyrosine kinase inhibitor is a Src family tyrosine kinase (SFK) inhibitor. In an embodiment of said transdermal patch, the tyrosine kinase inhibitor is selected from, but is not limited to, the group consisting of Dasatinib, Ponatinib, Saracatinib, Bosutinib, Rebastinib, Masitinib, Tirbanibulin, Bafetinib, SU6656 and Elzovanitinib and the PI3K / mTOR inhibitor is selected from, but is not limited to, the group consisting of bimiralisib (PQR309), Umbralisib, Buparlisib, PIK-75 hydrochloride, AZD 6482, VS-5584, Pilaralisib, SAR- 260301, Acalisib, Copanlisib, Pictilisib, Dactolisib, Inavolisib, Idelalisib, Duvelisib, Omipalisib, Taselisib and Voxtalisib. In some embodiments, the tyrosine kinase inhibitor is dasatinib and the PI3K / mTOR inhibitor is bimiralisib (PQR309). In some embodiments, the tyrosine kinase inhibitor is dasatinib and the PI3K / mTOR inhibitor is buparlisib. In various embodiments of the herein provided transdermal patch, the early-stage skin cancer in situ or the noninvasive precancerous lesion is actinic keratosis. In some embodiments of the transdermal patch, the early- stage skin cancer in situ or the noninvasive precancerous lesion is a squamous cell carcinoma in situ like lesion. In certain embodiments of the transdermal patch, the early-stage skin cancer in situP-637213-PC or the noninvasive precancerous lesion is associated with cutaneous squamous cell carcinoma. In a particular embodiment, the subject is human. In an embodiment, of the transdermal patch is administered to treat an invasive skin cancer lesion and / or to induce regression or remission of an invasive skin cancer lesion, including but not limited to, a basal cell carcinoma, a squamous cell carcinoma, or a Merkel cell carcinoma.

[0072] In some embodiments, the transdermal patches have the tyrosine kinase and the PI3K / mTOR inhibitors each present in a therapeutically effective amount of from 0.1 wt.% to 5 wt.% of the pharmaceutical composition in the transdermal patch. In some embodiments, the transdermal patches have the tyrosine kinase and the PI3K / mTOR inhibitors each present in a therapeutically effective amount of from 2 wt.% to 5 wt.% of the pharmaceutical composition in the transdermal patch. In certain embodiments, the transdermal patches have the tyrosine kinase and the PI3K / mTOR inhibitors each present in a therapeutically effective amount of from 0.1 wt.% to 0.5 wt.% of the pharmaceutical composition in the transdermal patch. In some embodiments, the transdermal patches have the tyrosine kinase and the PI3K / mTOR inhibitors each present in a therapeutically effective amount of from 0.5 wt.% to 5 wt.% of the pharmaceutical composition in the transdermal patch. In some embodiments, the transdermal patches have the tyrosine kinase and the PI3K / mTOR inhibitors each present in a therapeutically effective amount of from 0.5 wt.% to 2 wt.% of the pharmaceutical composition in the transdermal patch. In certain embodiments, the transdermal patches have the tyrosine kinase and the PI3K / mTOR inhibitors each present in a therapeutically effective amount of from 0.1 wt.% to 2 wt.% of the pharmaceutical composition in the transdermal patch. In some embodiments, the transdermal patch adheres to the skin or tissue and delivers a sustained release of the tyrosine kinase and the PI3K / mTOR inhibitors from three days up to one week after administration, i.e., application thereof.

[0073] Various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below find experimental support in the following examples, which are presented in order to more fully illustrate certain embodiments of the invention. They should in no way be construed, however, as limiting the broad scope of the invention.P-637213-PC EXAMPLES EXAMPLE 1 Combination Topical Kinase Inhibitors to Treat the Early Stages of UV-Induced Skin Cancer (Precancerous Lesions) in an In Vivo Transgenic Mouse Model of Skin Cancer

[0074] A combination of a tyrosine kinase inhibitor (dasatinib) and a PI3K / mTOR inhibitor (bimiralisib (PQR309)) were applied together topically to precancerous lesions in an in vivo skin cancer model.

[0075] A mixture of topical kinase inhibitors dasatinib 0.5% and birmiralisib (PQR309) 0.3% were applied in a DMSO solution to treat cutaneous squamous cell carcinoma in situ (cSCCs) in K14- Fyn Y528F transgenic mice. Topical kinase inhibitors were applied once per day to cSCCs and the area of the lesions was measured as a function of time. The number of cSCCs treated per cohort were: 17 mice were treated with dasatinib 0.5%, 20 mice were treated with birmiralisib 0.3%, and 17 mice were treated with the combination of dasatinib 0.5% and bimiralisib (PQR309) 0.3%.

[0076] As shown in Fig. 1, the combination of topical kinase inhibitors performed significantly better than each agent alone.

[0077] Given the complexity of signaling pathways in keratinocytes it was not clear if the combination of these two compounds together would induce quicker tumor regression since the PI3K / mTOR inhibitor acts downstream of the tyrosine kinases.

[0078] It was surprisingly and unexpectedly found that topically applying the aforementioned combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor was more effective than applying each single agent in inducing regression of cutaneous squamous cell carcinoma lesions in the K14 Fyn Y528F transgenic mouse model of skin cancer. EXAMPLE 2 Combinations of Topical Kinase Inhibitors to Treat cSCCs in an In Vivo Transgenic Mouse Model

[0079] Two different combinations of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor were applied together topically to precancerous lesions in an in vivo model of skin cancer.

[0080] A mixture of the topical kinase inhibitors dasatinib and birmiralisib was used to treat cutaneous squamous cell carcinoma in situ (cSCCs) in K14-Fyn Y528F transgenic mice and was compared with treatment of cSCCs with a combination of dasatinib and vemurafenib. TopicalP-637213-PC kinase inhibitor combinations were applied once per day to cSCCs and the area of the lesions was measured as a function of time.

[0081] A combination of 0.25% dasatinib and 0.8% vemurafenib was compared to a combination of 0.5% dasatinib and 0.5% birmiralisib. The total concentration of topical kinase inhibitors was one percent or 1.05% to treat cSCCs in K14-Fyn Y528F transgenic mouse, as shown in Figure 2.

[0082] The topical kinase inhibitors were applied once per day to cSCCs and the area of the lesions was measured as a function of time. As shown in Figure 2, it was found that the combination of topical kinase inhibitors dasatinib with vemurafenib is much less efficient in clearing cSCCs lesions than the two combinations of topical kinase inhibitors dasatinib 0.5% and birmiralisib 0.5% in a K14-Fyn Y528F transgenic mouse model. EXAMPLE 3 Combination of Topical Kinase Inhibitors to Treat cSCCs in an In Vivo Transgenic Mouse Model

[0083] Combinations of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor were applied together topically to precancerous lesions in an in vivo model of skin cancer.

[0084] Two separate mixtures of the topical kinase inhibitors dasatinib and birmiralisib were used to treat cutaneous squamous cell carcinoma in situ (cSCCs) in K14-Fyn Y528F transgenic mice and compared with a combination of dasatinib and vemurafenib. Topical kinase inhibitors were applied once per day to cSCCs and the area of the lesions was measured as a function of time.

[0085] Figure 3 shows a summary of the therapeutic effects of a combination of dasatinib 0.25% and 0.8% vemurafenib compared to 0.5% dasatinib and 0.5% birmiralisib, 0.5% dasatinib and 0.3% birmiralisib, and compared to single agent topical kinase inhibitors, 0.5% dasatinib and 0.3% birmiralisib, to treat cSCCs in K14-Fyn Y528F transgenic mouse. The topical kinase inhibitors were applied once per day to cSCCs and the area of the lesions was measured as a function of time. This combination of topical kinase inhibitors with vemurafenib was much less efficient in clearing lesions than either combination of topical kinase inhibitors dasatinib and birmiralisib and each single agent, dasatinib and birmiralisib alone.P-637213-PC EXAMPLE 4 Therapeutic Efficacy of a High Single Dose of a Combination of Topical Kinase Inhibitors to Treat cSCCs in an In Vivo Transgenic Mouse Model

[0086] Topical application of low doses of 0.5% dasatinib and 0.3% birmiralisib daily achieved synergistic clearance of invasive cSCCs in the K14-Fyn Y528F model using a gel or solution daily as shown in Example 1. Daily treatment using this combination for one week shrank the cSCCs by approximately 27%. Two weeks of treatment with the combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor shrank lesions by approximately 44%. These data indicated that there was synergistic clearance of cSCCs using a combination of a tyrosine kinase inhibitor and a PI3K / m / TOR inhibitor compared with either inhibitor alone. These data also suggested that higher doses of both kinase inhibitors in the combination may shrink the cSCCs more quickly and significantly.

[0087] To show that a single dose of higher concentrations of both inhibitors, dasatinib and buparlisib, treat actinic keratoses effectively, the efficacy of a single dose of 2.0% dasatinib and 2.0% buparlisib was determined on cSCCs, which are thicker than human actinic keratoses (AKs), in the K14-Fyn Y528F transgenic mouse model. Demonstrating that a single application of higher concentrations of each of these inhibitors achieve significant clearance of cSCCs in the K14-Fyn Y528F model, suggests that a similar dose could clear, smaller thinner lesions such as actinic keratoses. In an embodiment, a “high” concentration of each inhibitor, i.e., dasatinib and buparlisib, comprises a therapeutically effective amount of from 2 wt.% to 5 wt.% of the tyrosine kinase and the PI3K / mTOR inhibitors in a pharmaceutical composition for topical administration to a subject in need thereof, e.g., to an AK subject. In an embodiment, a “low” concentration of each inhibitor, i.e., dasatinib and buparlisib, comprises a therapeutically effective amount of from 0.1 wt.% to 0.5 wt.% of the tyrosine kinase and the PI3K / mTOR inhibitors in a pharmaceutical composition for topical administration to a subject in need thereof, e.g., to an AK subject.

[0088] A single dose of 2.0% dasatinib and 2.0% buparlisib was applied to 15 cSCCs and the tumor area was measured at time 0 and at the indicated time points shown in Figure 4. One application of 2.0% dasatinib and 2.0% buparlisib cleared approximately 31% of the cSCC tumor area in one week, p<0.005, N=15. These data demonstrate the feasibility of clearing actinic keratoses with a single high dose of a combination of the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor in patients. In a particular embodiment the tyrosine kinase inhibitor isP-637213-PC dasatinib and the PI3K / mTOR inhibitor is buparlisib and / or birmiralisib. The combination of higher doses of inhibitors, such as dasatinib with buparlisib and / or birmiralisib, could clear human early-stage skin cancer in situ or a noninvasive precancerous lesion such AKs with a single application of the combination and could be delivered to skin lesions topically as a gel / ointment, lotion, solution, foam, powder, paste, stick, cream, a spray, a spray-on patch, or a transdermal patch.

[0089] Overall, the data in Examples 1-4 demonstrate that unique combinations of topical kinase inhibitors when delivered together clear cSCCs efficiently and more efficiently than the respective single agents or other kinase inhibitor combinations. The combinations of birmiralisib and dasatinib and of buparlisib and dasatinib were particularly effective in clearing cSCCs in the animal skin cancer model.

[0090] Having described certain embodiments of the invention with reference to the accompanying drawings, it is to be understood that the invention is not limited to the precise embodiments, and that various modifications, substitutions, changes, and equivalents may be effected thereto by those skilled in the art without departing from the scope or spirit of the invention as defined in the appended claims.

Claims

P-637213-PC WHAT IS CLAIMED IS:

1. A method for treating an early-stage skin cancer in situ or a noninvasive precancerous lesion in a subject in need thereof, the method comprising topically administering to the subject a therapeutically effective amount of a combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor.

2. The method of claim 1, wherein the tyrosine kinase inhibitor is a Src family tyrosine kinase (SFK) inhibitor.

3. The method of claim 1, wherein the tyrosine kinase inhibitor is selected from the group consisting of Dasatinib, Ponatinib, Saracatinib, Bosutinib, Rebastinib, Masitinib, Tirbanibulin, Bafetinib, SU6656 and Elzovanitinib, and the PI3K / mTOR inhibitor is selected from the group consisting of bimiralisib (PQR309), Umbralisib, Buparlisib, PIK- 75 hydrochloride, AZD 6482, VS-5584, Pilaralisib, SAR-260301, Acalisib, Copanlisib, Pictilisib, Dactolisib, Inavolisib, Idelalisib, Duvelisib, Omipalisib, Taselisib and Voxtalisib.

4. The method of claim 1, wherein the early-stage skin cancer in situ or the noninvasive precancerous lesion is selected from the group consisting of an actinic keratosis, a squamous cell carcinoma in situ like lesion, a cutaneous squamous cell carcinoma, and a keratinocyte hyperproliferation skin disorder, wherein the keratinocyte hyperproliferation skin disorder is psoriasis, lichen simplex chronicus, seborrheic keratoses, porokeratosis, lichen planus or verrucae (warts).

5. The method of claim 1, wherein the subject is human.

6. The method of claim 1, further comprising treating the subject with at least one other treatment regime selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, photodynamic therapy, electrocautery, laser therapy, cryosurgery, and surgery.

7. The method of claim 1, wherein the combination of the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor is administered concurrently.

8. The method of claim 1, wherein the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor are each administered individually.P-637213-PC 9. The method of claim 1, wherein the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor are each administered daily.

10. The method of claim 1, wherein the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor are each administered once.

11. The method of claim 1, wherein each of the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor are administered in an amount of from 0.1 wt.% to 5 wt.% of a pharmaceutical composition comprising the tyrosine kinase and the PI3K / mTOR inhibitors.

12. The method of claim 1, wherein each of the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor are administered in an amount of from 2 wt.% to 5 wt.% of a pharmaceutical composition comprising the tyrosine kinase and the PI3K / mTOR inhibitors.

13. The method of claim 1, wherein each of the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor are administered in an amount of from 0.1 wt.% to 0.5 wt.% of a pharmaceutical composition comprising the tyrosine kinase and the PI3K / mTOR inhibitors.

14. A method for inducing regression or achieving clearance of an early-stage skin cancer in situ or a noninvasive precancerous lesion in a subject in need thereof, the method comprising topically administering to the subject a therapeutically effective amount of a combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor.

15. The method of claim 14, wherein the tyrosine kinase inhibitor is a Src family tyrosine kinase (SFK) inhibitor.

16. The method of claim 14, wherein the tyrosine kinase inhibitor is selected from the group consisting of Dasatinib, Ponatinib, Saracatinib, Bosutinib, Rebastinib, Masitinib, Tirbanibulin, Bafetinib, SU6656 and Elzovanitinib, and the PI3K / mTOR inhibitor is selected from the group consisting of bimiralisib (PQR309), Umbralisib, Buparlisib, PIK- 75 hydrochloride, AZD 6482, VS-5584, Pilaralisib, SAR-260301, Acalisib, Copanlisib, Pictilisib, Dactolisib, Inavolisib, Idelalisib, Duvelisib, Omipalisib, Taselisib and Voxtalisib.

17. The method of claim 14, wherein the early-stage skin cancer in situ or the noninvasive precancerous lesion is selected from the group consisting of an actinic keratosis, a squamous cell carcinoma in situ like lesion, a cutaneous squamous cell carcinoma, and aP-637213-PC keratinocyte hyperproliferation skin disorder, wherein the keratinocyte hyperproliferation skin disorder is psoriasis, lichen simplex chronicus, seborrheic keratoses, porokeratosis, lichen planus or verrucae (warts).

18. The method of claim 14, wherein the subject is human.

19. The method of claim 14, further comprising treating the subject with at least one other treatment regime selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, photodynamic therapy, electrocautery, laser therapy, cryosurgery, and surgery.

20. The method of claim 14, wherein the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor are each administered daily.

21. The method of claim 14, wherein the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor are each administered once.

22. The method of claim 14, wherein each of the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor are administered in an amount of from 0.1 wt.% to 2 wt.% of a pharmaceutical composition comprising the tyrosine kinase and the PI3K / mTOR inhibitors.

23. The method of claim 14, wherein each of the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor are administered in an amount of from 2 wt.% to 20 wt.% of a pharmaceutical composition comprising the tyrosine kinase and the PI3K / mTOR inhibitors.

24. A pharmaceutical composition comprising a therapeutically effective amount of a combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor, and a pharmaceutically acceptable carrier.

25. The pharmaceutical composition of claim 24, wherein the tyrosine kinase inhibitor is a Src family tyrosine kinase (SFK) inhibitor.

26. The pharmaceutical composition of claim 24, wherein the tyrosine kinase inhibitor is selected from the group consisting of Dasatinib, Ponatinib, Saracatinib, Bosutinib, Rebastinib, Masitinib, Tirbanibulin, Bafetinib, SU6656 and Elzovanitinib and the PI3K / mTOR inhibitor is selected from the group consisting of bimiralisib (PQR309), Umbralisib, Buparlisib, PIK-75 hydrochloride, AZD 6482, VS-5584, Pilaralisib, SAR-P-637213-PC 260301, Acalisib, Copanlisib, Pictilisib, Dactolisib, Inavolisib, Idelalisib, Duvelisib, Omipalisib, Taselisib and Voxtalisib.

27. The pharmaceutical composition of claim 24 formulated as an ointment, gel, cream, solution, lotion, foam, powder, paste, stick, spray, spray-on patch, or a transdermal patch.

28. The pharmaceutical composition of claim 24 formulated in liposomes.

29. A spray-on patch or a transdermal patch for treating an early-stage skin cancer in situ or a noninvasive precancerous lesion, the spray-on patch or transdermal patch comprising a pharmaceutical composition comprising a therapeutically effective amount of a combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor.

30. The spray-on patch or transdermal patch of claim 29, wherein the tyrosine kinase inhibitor is a Src family tyrosine kinase (SFK) inhibitor.

31. The spray-on patch or transdermal patch of claim 29, wherein the tyrosine kinase inhibitor is selected from the group consisting of Dasatinib, Ponatinib, Saracatinib, Bosutinib, Rebastinib, Masitinib, Tirbanibulin, Bafetinib, SU6656 and Elzovanitinib, and the PI3K / mTOR inhibitor is selected from the group consisting of bimiralisib (PQR309), Umbralisib, Buparlisib, PIK-75 hydrochloride, AZD 6482, VS-5584, Pilaralisib, SAR- 260301, Acalisib, Copanlisib, Pictilisib, Dactolisib, Inavolisib, Idelalisib, Duvelisib, Omipalisib, Taselisib and Voxtalisib.

32. The spray-on patch or transdermal patch of claim 29, wherein the early-stage skin cancer in situ or the noninvasive precancerous lesion is selected from the group consisting of an actinic keratosis, a squamous cell carcinoma in situ like lesion, a cutaneous squamous cell carcinoma, and a keratinocyte hyperproliferation skin disorder, wherein the keratinocyte hyperproliferation skin disorder is psoriasis, lichen simplex chronicus, seborrheic keratoses, porokeratosis, lichen planus or verrucae (warts) 33. The spray-on patch or transdermal patch of claim 29, wherein the early-stage skin cancer in situ or the noninvasive precancerous lesion is a squamous cell carcinoma in situ like lesion.P-637213-PC 34. The spray-on patch or transdermal patch of claim 29, wherein the early-stage skin cancer in situ or the noninvasive precancerous lesion is associated with cutaneous squamous cell carcinoma.

35. The spray-on patch or transdermal patch of claim 29, wherein the subject is human.

36. The spray-on patch or transdermal patch of claim 29, wherein each of the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor are administered in an amount of from 0.1 wt.% to 5 wt.% of the pharmaceutical composition comprising the tyrosine kinase and the PI3K / mTOR inhibitors.

37. The spray-on patch or transdermal patch of claim 29, wherein each of the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor are administered in an amount of from 2 wt.% to 5 wt.% of a pharmaceutical composition comprising the tyrosine kinase and the PI3K / mTOR inhibitors.

38. The spray-on patch or transdermal patch of claim 29, wherein each of the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor are administered in an amount of from 0.1 wt.% to 0.5 wt.% of a pharmaceutical composition comprising the tyrosine kinase and the PI3K / mTOR inhibitors.

39. A method for treating an invasive skin cancer lesion in a subject in need thereof, the method comprising topically administering to the subject a therapeutically effective amount of a combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor.

40. The method of claim 39, wherein the tyrosine kinase inhibitor is a Src family tyrosine kinase (SFK) inhibitor.

41. The method of claim 39, wherein the tyrosine kinase inhibitor is selected from the group consisting of Dasatinib, Ponatinib, Saracatinib, Bosutinib, Rebastinib, Masitinib, Tirbanibulin, Bafetinib, SU6656 and Elzovanitinib, and the PI3K / mTOR inhibitor is selected from the group consisting of bimiralisib (PQR309), Umbralisib, Buparlisib, PIK- 75 hydrochloride, AZD 6482, VS-5584, Pilaralisib, SAR-260301, Acalisib, Copanlisib, Pictilisib, Dactolisib, Inavolisib, Idelalisib, Duvelisib, Omipalisib, Taselisib and Voxtalisib.P-637213-PC 42. The method of claim 39, wherein the invasive skin cancer lesion is a basal cell carcinoma, a squamous cell carcinoma, or a Merkel cell carcinoma.

43. The method of claim 39, wherein the subject is human.

44. The method of claim 39, further comprising treating the subject with at least one other treatment regime selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, photodynamic therapy, electrocautery, laser therapy, cryosurgery, and surgery.

45. The method of claim 39, wherein the combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor is administered concurrently.

46. The method of claim 39, wherein the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor are each administered individually.

47. The method of claim 39, wherein the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor are each administered daily.

48. The method of claim 39, wherein the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor are each administered once.

49. The method of claim 39, wherein each of the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor are administered in an amount of from 0.1 wt.% to 5 wt.% of a pharmaceutical composition comprising the tyrosine kinase and the PI3K / mTOR inhibitors.

50. The method of claim 39, wherein each of the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor are administered in an amount of from 2 wt.% to 5 wt.% of a pharmaceutical composition comprising the tyrosine kinase and the PI3K / mTOR inhibitors.

51. The method of claim 39, wherein each of the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor are administered in an amount of from 0.1 wt.% to 0.5 wt.% of a pharmaceutical composition comprising the tyrosine kinase and the PI3K / mTOR inhibitors.

52. A method for inducing regression or remission of an invasive skin cancer lesion in a subject in need thereof, the method comprising topically administering to the subject a therapeutically effective amount of a combination of a tyrosine kinase inhibitor and a PI3K / mTOR inhibitor.P-637213-PC 53. The method of claim 52, wherein the tyrosine kinase inhibitor is a Src family tyrosine kinase (SFK) inhibitor.

54. The method of claim 52, wherein the tyrosine kinase inhibitor is selected from the group consisting of Dasatinib, Ponatinib, Saracatinib, Bosutinib, Rebastinib, Masitinib, Tirbanibulin, Bafetinib, SU6656 and Elzovanitinib, and the PI3K / mTOR inhibitor is selected from the group consisting of bimiralisib (PQR309), Umbralisib, Buparlisib, PIK- 75 hydrochloride, AZD 6482, VS-5584, Pilaralisib, SAR-260301, Acalisib, Copanlisib, Pictilisib, Dactolisib, Inavolisib, Idelalisib, Duvelisib, Omipalisib, Taselisib and Voxtalisib.

55. The method of claim 52, wherein the invasive skin cancer lesion is a basal cell carcinoma, a squamous cell carcinoma or a Merkel cell carcinoma.

56. The method of claim 52, wherein the subject is human.

57. The method of claim 52, further comprising treating the subject with at least one other treatment regime selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, photodynamic therapy, electrocautery, laser therapy, cryosurgery, and surgery.

58. The method of claim 52, wherein each of the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor are administered in an amount of from 0.1 wt.% to 5 wt.% of a pharmaceutical composition comprising the tyrosine kinase and the PI3K / mTOR inhibitors.

59. The method of claim 52, wherein each of the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor are administered in an amount of from 2 wt.% to 5 wt.% of a pharmaceutical composition comprising the tyrosine kinase and the PI3K / mTOR inhibitors.

60. The method of claim 52, wherein each of the tyrosine kinase inhibitor and the PI3K / mTOR inhibitor are administered in an amount of from 0.1 wt.% to 0.5 wt.% of a pharmaceutical composition comprising the tyrosine kinase and the PI3K / mTOR inhibitors.

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